Background: Pain relief during labor is a part of standard care in modern obstetrics. Several modalities used for pain relief have their own disadvantages and benefits in terms of side effects, effectiveness, availability, and satisfaction. The objectives of this study are primarily to compare the effectiveness and patients’ satisfaction for pain relief during labor between pethidine and inhaled 50% nitrous oxide (Entonox®). Methods: Laboring women at 37–41 + 6 weeks of gestation were randomly allocated to receive pethidine (50 mg intravenously) or Entonox® for reducing labor pain. Pain scores were evaluated at 0, (baseline), 30, 60, 90, and 120 min after initiation, using the visual analog scale (VAS) and also satisfaction score after delivery using the verbal rating scale (VRS). The secondary outcomes were also assessed, including APGAR scores, labor course, side effects, and cesarean section rate. Results: A total of 136 laboring women underwent randomization into two groups, but only 58 and 65 in the pethidine group and the Entonox® group were available for analysis. The median pain scores at baseline, 30, 60, and 90 min were comparable between both groups (p-value > 0.05); however, pain score at 120 min in the pethidine group was significantly higher (p-value: 0.038). The median of satisfaction score was significantly higher in the Entonox® group (4 vs. 3; p-value 0.043). All of the secondary outcomes were comparable between the two groups. Conclusions: Both have comparable effectiveness, but Entonox® has a higher satisfaction score. Entonox® could be an alternative to pethidine for reducing labor pain, because of its efficacy, ease for self-adjustment for satisfaction, and no serious effects on the labor course and newborns.